CHD2Chromodomain helicase DNA binding protein 2

Score

Autism Reports / Total Reports

Rare Variants / Common Variants

Aliases

CHD2, EEOC

Associated Syndromes

Tourette syndrome

Genetic Category

Rare Single Gene Mutation, Syndromic

Chromosome Band

15q26.1

Associated Disorders

EP, ASD, EPS, DD/NDD, ADHD, ID

Relevance to Autism

Six de novo variants in the CHD2 gene (four truncating variants and two missense variants disrupting highly conserved residues in the SNF2-related helicase/ATPase domain) were identified in individuals with a wide range of epileptic encephalopathies; all six of these individuals exhibited moderate-to-severe intellectual disability, and two individuals also displayed ASD (Carvill et al., 2013). De novo variants affecting this gene have also been found in individuals with ASD (Neale et al., 2012) and intellectual disability (Rauch et al., 2012).

Molecular Function

The CHD family of proteins is characterized by the presence of chromo (chromatin organization modifier) domains and SNF2-related helicase/ATPase domains. CHD genes alter gene expression possibly by modification of chromatin structure thus altering access of the transcriptional apparatus to its chromosomal DNA template.

SFARI Gene score

High Confidence, Syndromic

Score Delta: Decreased from 2S to 1.1 + S

criteria met

High Confidence

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

10/1/2017

2S

2S

Decreased from 2S to 2S

Description

De novo loss-of-function and missense variants in the CHD2 gene have been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (PMIDs 23020937, 23708187, 23934111, and 24207121). Two cases with de novo LoF CHD2 variants also presented with ASD (PMIDs 23708187 and 24207121). De novo deletions affecting CHD2 have also been identified in 4 patients with recurrent clinical symptoms such as epilepsy, developmental delay/intellectual disability, and behavioral problem, including ASD in one case (PMID 24834135). Two additional de novo LoF variants in the CHD2 gene (one nonsense, one frameshift) were recently identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Reports Added

7/1/2017

2S

2S

Decreased from 2S to 2S

Description

De novo loss-of-function and missense variants in the CHD2 gene have been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (PMIDs 23020937, 23708187, 23934111, and 24207121). Two cases with de novo LoF CHD2 variants also presented with ASD (PMIDs 23708187 and 24207121). De novo deletions affecting CHD2 have also been identified in 4 patients with recurrent clinical symptoms such as epilepsy, developmental delay/intellectual disability, and behavioral problem, including ASD in one case (PMID 24834135). Two additional de novo LoF variants in the CHD2 gene (one nonsense, one frameshift) were recently identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Reports Added

4/1/2017

2S

2S

Decreased from 2S to 2S

Description

De novo loss-of-function and missense variants in the CHD2 gene have been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (PMIDs 23020937, 23708187, 23934111, and 24207121). Two cases with de novo LoF CHD2 variants also presented with ASD (PMIDs 23708187 and 24207121). De novo deletions affecting CHD2 have also been identified in 4 patients with recurrent clinical symptoms such as epilepsy, developmental delay/intellectual disability, and behavioral problem, including ASD in one case (PMID 24834135). Two additional de novo LoF variants in the CHD2 gene (one nonsense, one frameshift) were recently identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

1/1/2017

2S

2S

Decreased from 2S to 2S

Description

De novo loss-of-function and missense variants in the CHD2 gene have been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (PMIDs 23020937, 23708187, 23934111, and 24207121). Two cases with de novo LoF CHD2 variants also presented with ASD (PMIDs 23708187 and 24207121). De novo deletions affecting CHD2 have also been identified in 4 patients with recurrent clinical symptoms such as epilepsy, developmental delay/intellectual disability, and behavioral problem, including ASD in one case (PMID 24834135). Two additional de novo LoF variants in the CHD2 gene (one nonsense, one frameshift) were recently identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Reports Added

10/1/2016

2S

2S

Decreased from 2S to 2S

Description

De novo loss-of-function and missense variants in the CHD2 gene have been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (PMIDs 23020937, 23708187, 23934111, and 24207121). Two cases with de novo LoF CHD2 variants also presented with ASD (PMIDs 23708187 and 24207121). De novo deletions affecting CHD2 have also been identified in 4 patients with recurrent clinical symptoms such as epilepsy, developmental delay/intellectual disability, and behavioral problem, including ASD in one case (PMID 24834135). Two additional de novo LoF variants in the CHD2 gene (one nonsense, one frameshift) were recently identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Reports Added

7/1/2016

2S

2S

Decreased from 2S to 2S

Description

De novo loss-of-function and missense variants in the CHD2 gene have been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (PMIDs 23020937, 23708187, 23934111, and 24207121). Two cases with de novo LoF CHD2 variants also presented with ASD (PMIDs 23708187 and 24207121). De novo deletions affecting CHD2 have also been identified in 4 patients with recurrent clinical symptoms such as epilepsy, developmental delay/intellectual disability, and behavioral problem, including ASD in one case (PMID 24834135). Two additional de novo LoF variants in the CHD2 gene (one nonsense, one frameshift) were recently identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Reports Added

1/1/2016

2S

2S

Decreased from 2S to 2S

Description

De novo loss-of-function and missense variants in the CHD2 gene have been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (PMIDs 23020937, 23708187, 23934111, and 24207121). Two cases with de novo LoF CHD2 variants also presented with ASD (PMIDs 23708187 and 24207121). De novo deletions affecting CHD2 have also been identified in 4 patients with recurrent clinical symptoms such as epilepsy, developmental delay/intellectual disability, and behavioral problem, including ASD in one case (PMID 24834135). Two additional de novo LoF variants in the CHD2 gene (one nonsense, one frameshift) were recently identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

1/1/2015

2S

2S

Decreased from 2S to 2S

Description

De novo loss-of-function and missense variants in the CHD2 gene have been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (PMIDs 23020937, 23708187, 23934111, and 24207121). Two cases with de novo LoF CHD2 variants also presented with ASD (PMIDs 23708187 and 24207121). De novo deletions affecting CHD2 have also been identified in 4 patients with recurrent clinical symptoms such as epilepsy, developmental delay/intellectual disability, and behavioral problem, including ASD in one case (PMID 24834135). Two additional de novo LoF variants in the CHD2 gene (one nonsense, one frameshift) were recently identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Reports Added

10/1/2014

3S

2S

Decreased from 3S to 2S

Description

De novo loss-of-function and missense variants in the CHD2 gene have been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (PMIDs 23020937, 23708187, 23934111, and 24207121). Two cases with de novo LoF CHD2 variants also presented with ASD (PMIDs 23708187 and 24207121). De novo deletions affecting CHD2 have also been identified in 4 patients with recurrent clinical symptoms such as epilepsy, developmental delay/intellectual disability, and behavioral problem, including ASD in one case (PMID 24834135). Two additional de novo LoF variants in the CHD2 gene (one nonsense, one frameshift) were recently identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

7/1/2014

No data

3S

Increased from No data to 3S

Description

De novo loss-of-function and missense variants in the CHD2 gene have been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (PMIDs 23020937, 23708187, 23934111, and 24207121). Two cases with de novo LoF CHD2 variants also presented with ASD (PMIDs 23708187 and 24207121). De novo deletions affecting CHD2 have also been identified in 4 patients with recurrent clinical symptoms such as epilepsy, developmental delay/intellectual disability, and behavioral problem, including ASD in one case (PMID 24834135)

4/1/2014

No data

3S

Increased from No data to 3S

Description

De novo loss-of-function and missense variants in the CHD2 gene have been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (PMIDs 23020937, 23708187, 23934111, and 24207121). Two cases with de novo LoF CHD2 variants also presented with ASD (PMIDs 23708187 and 24207121). De novo deletions affecting CHD2 have also been identified in 4 patients with recurrent clinical symptoms such as epilepsy, developmental delay/intellectual disability, and behavioral problem, including ASD in one case (PMID 24834135)

Krishnan Probability Score

Score 0.47577089053778

Ranking 8536/25841 scored genes

[Show Scoring Methodology]

Krishnan and colleagues generated probability scores genome-wide by using a machine learning
approach on a human brain-specific gene network. The method was first presented in Nat
Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed
in column G of supplementary table 3 (see:
http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser,
with the ability to view networks of associated ASD risk genes, can be found at
asd.princeton.edu.

ExAC Score

Score 0.99999999884542

Ranking 100/18225 scored genes

[Show Scoring Methodology]

The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has
been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by
Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at
exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of-
function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of-
function mutations in autism in such a gene would be more likely to confer risk. For a full list of
pLI scores see:
ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle
aned_exac_nonTCGA_z_pli_rec_null_data.txt

Iossifov Probability Score

Score 0.997

Ranking 12/239 scored genes

[Show Scoring Methodology]

Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists
239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This
probability metric combines the evidence from de novo likely-gene- disrupting and missense
mutations and assesses it against the background mutation rate in unaffected individuals from the
University of Washingtonâs Exome Variant Sequence database (evs.gs.washington.edu/EVS/).
The list of probability scores can be found here:
www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/-
/DCSupplemental/pnas.1516376112.sd02.xlsx

Sanders TADA Score

Score 6.7367674090958E-6

Ranking 7/18665 scored genes

[Show Scoring Methodology]

The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013),
and is a statistic that integrates evidence from both de novo and transmitted mutations.
It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233
(2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper
(the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).

Larsen Cumulative Evidence Score

Score 63

Ranking 24/461 scored genes

[Show Scoring Methodology]

Larsen and colleagues generated gene scores based on the sum of evidence for all available
ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size,
and variant frequency in the general population. The approach was first presented in Mol Autism
7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from
that paper.

Zhang D Score

Score 0.57451349814661

Ranking 156/20870 scored genes

[Show Scoring Methodology]

The DAMAGES score (disease-associated mutation analysis using gene expression signatures),
or D score, was developed to combine evidence from de novo loss-of- function mutation with
evidence from cell-type- specific gene expression in the mouse brain (specifically translational
profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with
positive D scores are more likely to be associated with autism risk, with higher-confidence genes
having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204-
215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in
supplementary table 2 from that paper.